Pulmonary arterial hypertension (PAH), is a fatal disease characterized by a pseudo-malignant phenotype. We investigated the expression and the role of the receptor tyrosine kinase Axl in experimental (i.e., monocrotaline and Su5416/hypoxia treated rats) and clinical PAH. In vitro Axl inhibition by R428 and Axl knock-down inhibited growth factor-driven proliferation and migration of non-PAH and PAH PASMCs. Conversely, Axl overexpression conferred a growth advantage. Axl declined in PAECs of PAH patients. Axl blockage inhibited BMP9 signaling and increased PAEC apoptosis, while BMP9 induced Axl phosphorylation. Gas6 induced SMAD1/5/8 phosphorylation and ID1/ID2 increase were blunted by BMP signaling obstruction. Axl association with BMPR2 was facilitated by Gas6/BMP9 stimulation and diminished by R428. In vivo R428 aggravated right ventricular hypertrophy and dysfunction, abrogated BMPR2 signaling, elevated pulmonary endothelial cell apoptosis and loss. Together, Axl is a key regulator of endothelial BMPR2 signaling and potential determinant of PAH.
- Novoyatleva, T.
- Rai, N.
- Kojonazarov, B.
- Veeroju, S.
- Ben-Batalla, I.
- Caruso, P.
- Shihan, M.
- Presser, N.
- Götz, E.
- Lepper, C.
- Herpel, S.
- Manaud, G.
- Perros, F.
- Gall, H.
- Ghofrani, H. A.
- Weissmann, N.
- Grimminger, F.
- Wharton, J.
- Wilkins, M.
- Upton, P. D.
- Loges, S.
- Morrell, N. W.
- Seeger, W.
- Schermuly, R. T.
